Lower CVR associated with higher white matter hyperintensity volume

Key markers of small vessel disease (SVD) were related to cerebrovascular reactivity (CVR), blood flow, and vascular and cerebrospinal fluid (CSF) pulsatility in patients with minor stroke, an imaging study showed.

“CVR is a measure of dynamic vessel function, with impairment reflecting an inability to increase blood flow when required,” wrote Joanna Wardlaw, MD, of the University of Edinburgh and coauthors in Neurology.

“Lower CVR, higher venous pulsatility, and lower foramen magnum CSF stroke volume indicate that dynamic vascular dysfunctions underpin PVS dysfunction and WMH development,” they noted.

“We did not find associations of CVR with lacunes or microbleeds,” Wardlaw and colleagues added. “This may be due to lack of statistical power but could also reflect different mechanisms driving development of different SVD imaging features.”

In results adjusted for age, sex, and systolic blood pressure, lower white matter CVR was associated with:

  • Higher white matter hyperintensity volume (WMH; −0.01%/mm Hg per log10 increase in WMH volume, P = 0.02).
  • Basal ganglia perivascular space (PVS; −0.01%/mmHg per point increase in the PVS score, P = 0.02).
  • Higher venous pulsatility (superior sagittal sinus −0.03%/mmHg, P = 0.02, per unit increase in the pulsatility index).

Lower foramen magnum CSF stroke volume was associated with worse white matter CVR (0.04%/mm Hg per mL increase in stroke volume, P = 0.04) and suggested more severe basal ganglia PVS (P = 0.09).

“CVR reflects both vessel stiffness and endothelial function,” noted C. Elizabeth Shaaban, PhD, MPH, of the University of Pittsburgh, and Jeremy Molad, MD, of the Tel-Aviv Sourasky Medical Center, in an accompanying editorial.

“The pulsatile waveform of blood should be dampened by the highly elastic aorta and large arteries as flow proceeds to the small vessels, but when vessels become less elastic, as with aging, their dampening ability is compromised, and highly pulsatile flow is transmitted to the cerebral small vessels with attendant negative consequences,” they wrote. “If unable to respond to vasodilatory stimulus with the appropriate blood supply to meet metabolic demand, the vasculature cannot maintain the health of the cerebral vessels and tissue.”

“Thus, pulsatility and CVR may have critical implications for SVD,” they added.

CVR measures the vasculature’s ability to respond to metabolic demands, and can be assessed by measuring how blood flow responds to a vasoactive stimulus like breathing carbon dioxide. Both transcranial doppler and functional MRI imaging have been used to gauge CVR.

SVD — pathology of small arteries, arterioles, capillaries, venules, and veins — is associated with an increased risk of stroke, dementia, and mortality, and increases with age and cardiovascular risk factors. Structural MRI markers of SVD capture parenchymal damage as WMH, PVS enlargement, lacunes, and cerebral microbleeds (CMBs). A 2016 review and meta-analysis found that cross-sectional WMH volume was greater with lower cerebral blood flow, but that evidence for lower blood flow preceding white matter hyperintensity was conflicting, and authors of that study recommended longitudinal studies be done. A recent study suggested one mechanism relating hypertension and SVD is elevated nighttime blood pressures (“reverse dipping”).

Wardlaw and colleagues recruited 53 patients (mean age 68, 74% male, 75% with hypertension) presenting with minor stroke (modified Rankin Score 3 or less; moderate disability but can walk without another person’s assistance) between October 2014 and April 2016, and studied them at least 1 month after acute stroke (median 92 days) using blood oxygen level depending (BOLD) MRI with CO2 challenge to determine CVR. Phase-contrast MRI measured pulsatility in the internal carotid arteries and intracranial venous sinuses as well as CSF flow and total cerebral blood flow (CBF).

The study found no association of resting cerebral blood flow with lower CVR or any measure of SVD. Relationships were more significant, although often not of greater magnitude, for white matter CVR than gray matter CVR.

“It is notable that all the associations of demographic and SVD features with impaired CVR were stronger in the white matter than the gray matter despite white matter CVR being around one-third the magnitude of that in gray matter and white matter CBF being around half of that in gray matter,” the authors wrote. “The directionality of CVR changes in gray matter is similar to white matter, however, and therefore, lack of statistical significance may reflect lack of power in this sample.”

While the study is limited by its small sample size, it “lays important groundwork for future longitudinal studies of hemodynamic factors and SVD in larger, diverse samples,” the editorialists wrote. “Developing effective interventions for SVD requires identifying targets for intervention and measurable biomarkers of the disease,” they noted, and this study has “added important additional candidates for both with these novel and important results.”

  1. Key markers of small vessel disease (SVD) were related to cerebrovascular reactivity (CVR), blood flow, and vascular and CSF pulsatility in patients with minor stroke, an imaging study showed.

  2. In results adjusted for age, sex, and systolic blood pressure, lower white matter CVR was associated with higher white matter hyperintensity volume, basal ganglia perivascular space, and higher venous pulsatility in the superior sagittal sinus.

Paul Smyth, MD, Contributing Writer, BreakingMED™

Funding for the study was provided by the Chief Scientist Office (Scotland) and the Wellcome Trust—University of Edinburgh Institutional Strategic Support Fund.

Wardlaw acknowledges support from the MRC UK Dementia Research Institute, the Fondation Leducq, and the Row Fogo Charitable Trust.

Shaaban has received NIA grants. Molad has no disclosures.

Cat ID: 38

Topic ID: 82,38,8,38,192,925